Chirality plays an essential role in nature and throughout the chemical sciences. Enantioselective synthesis and analysis of chiral compounds have become central aspects of drug discovery, material sciences, and other rapidly expanding research areas. The importance of chiral compounds in the pharmaceutical industry and other fields has stimulated the development of numerous asymmetric catalysts and reaction strategies (14 GAWLEY & AUBÉ, Principles of Asymmetric Synthesis, in TETRAHEDRON ORGANIC CHEMISTRY SERIES (J. E. Baldwin & P. D. Magnus eds., 1996); CHRISTIAN WOLF, DYNAMIC STEREOCHEMISTRY OF CHIRAL COMPOUNDS 180-398 (2008)). Optimization efforts typically entail elaborate chiral ligand modifications to fine-tune the catalyst in addition to conventional screening of a wide range of reaction parameters.
The introduction of tropos ligands such as biphenol phosphite (Reetz & Neugebauer, Angew. Chem. Int. Ed. 38:179-81 (1999); Blackmond et al., Angew. Chem. Int. Ed. 38:2196-99 (1999); Reetz & Li, Angew. Chem. Int. Ed. 44:2959-62 (2005)), DPPF (Mikami & Aikawa, Org. Lett. 4:99-101 (2002)), BIPHEP (Ohkuma et al., J. Am. Chem. Soc. 120:1086-87 (1998); Mikami et al., Angew. Chem. Int. Ed. 38:495-97 (1999); Becker et al., J. Am. Chem. Soc. 123:9478-79 (2001); Aikawa & Mikami, Angew. Chem. Int. Ed. 42:5455-58 (2003); Aikawa & Mikami, Angew. Chem. Int. Ed. 42:5458-61 (2003); Mikami et al., Angew. Chem. Int. Ed. 44:7257-60 (2005); Aikawa et al., Angew. Chem. Int. Ed. 48:6073-77 (2009)), and BIPHOS (Tissot et al., Angew. Chem. Int. Ed. 40:1076-78 (2001)) to asymmetric catalysis has greatly facilitated these efforts and led to a variety of highly effective reactions (Aikawa & Mikami, Review, Chem. Commun. 48:11050-69 (2012)) (selected examples of tropos ligands used in asymmetric catalysis are shown below).

An important feature of tropos ligands is that they exist as a mixture of rapidly interconverting rotamers at room temperature (CHRISTIAN WOLF, DYNAMIC STEREOCHEMISTRY OF CHIRAL COMPOUNDS 292 (2008)). In many cases, addition of an enantiopure diamine or another activator to a metal complex carrying a tropos ligand, for example [(DPPF)Pd(II)], affords chiral catalysts that give exceptional yields and ee's in hydrogenation, Diels-Alder, ene, and other reactions. The presence of a stereodynamic ligand in the coordination sphere of a chiral metal complex often favors the population of a distinct conformation or configuration, and this chiral amplification process can ultimately enhance the asymmetric induction process (CHRISTIAN WOLF, DYNAMIC STEREOCHEMISTRY OF CHIRAL COMPOUNDS 180-398 (2008)). Because many tropos ligands are readily available and inexpensive compared to their nonracemizable enantiopure analogues, the optimization of the ee of a catalytic reaction by screening of tropos additives is economically attractive and has been adapted by many laboratories.
Cobalt complexes carrying chiral N,N′-bis(salicylidene)ethylenediamine (salen) ligands have also been used very successfully as polymerization catalysts (Nakano et al., Angew. Chem. Int. Ed. 50:4868-71 (2011); Jeon et al., Dalton Trans. 42:9245-54 (2013); Wu et al., Macromolecules 46:2128-33 (2013)) and in asymmetric catalytic reactions (Canali & Sherrington, Chem. Soc. Rev. 28:85-93 (1999); Baleizão & Garcia, Chem. Rev. 106:3987-4043 (2006); Decortes et al., Angew. Chem. Int. Ed. 49:9822-37 (2010)). Impressive results have been reported by Jacobsen and others with epoxide desymmetrizations (Birrell & Jacobsen, Org. Lett. 78:2895-97 (2013)), and hydrolytic (Tokunaga et al., Science 277:936-38 (1997); Schaus et al., J. Am. Chem. Soc. 124:1307-15 (2002); Liu et al., J. Am. Chem. Soc. 133:14260-63 (2011); Ford et al., J. Am. Chem. Soc. 135:15595-608 (2013)) or aminolytic (Kumar et al., J. Org. Chem. 78:9076-84 (2013)) kinetic resolutions of epoxides (Bredihhina et al., J. Org. Chem. 78:2379-85 (2013)). The general usefulness of chiral (salen)cobalt complexes in asymmetric catalysis has inspired several enantioselective recognition (Mizuno et al., Tetrahedron 55:9455-68 (1999)) and resolution studies (Fujii et al., Bull. Chem. Soc. Jpn. 54:2029-38 (1981); Fujii et al., J. Chem. Soc. Chem. Commun. 7:415-17 (1985)). For example, it has been shown that the lipophilic cobalt(III) complex derived from the C2-symmetric salen 3 (see Example 26 for structure), which is a very effective catalyst in hydrolytic kinetic resolutions of terminal epoxides, can be used for practical separation of racemic N-benzyl α-amino acids via liquid-liquid extraction (Dzygiel et al., Eur. J. Org. Chem. 1253-64 (2008)). It has also been demonstrated that the cobalt(III) complex of the asymmetric ligand 4 (see Example 26 for structure) has potential for enantioselective differentiation of unprotected chiral amino alcohols (Kim et al., J. Am. Chem. Soc. 127:16776-77 (2005)).
The advance of combinatorial methods and automated synthesis allows the production of large numbers of chiral samples literally overnight. The steadily increasing efficiency in asymmetric synthesis has shifted focus toward the development of time efficient optical techniques with potential for high-throughput screening (Leung et al., Chem. Soc. Rev. 41:448 (2012)). In contrast to the advance of asymmetric synthesis, which is partly due to the widespread use of combinatorial methods that yield large numbers of chiral samples overnight, the analysis of the enantiomeric composition of chiral products is typically time-consuming and delays the discovery progress (Leung et al., Chem. Soc. Rev. 41:448-79 (2012)). Several groups have begun to address this bottleneck with the development of optical methods based on fluorescence (Lee & Lin, J. Am. Chem. Soc. 124:4554-55 (2002); Lin et al., J. Am. Chem. Soc. 124:2088-89 (2002); Mei & Wolf, Chem. Commun. 2078-79 (2004); Zhao et al., Angew. Chem. Int. Ed. 43:3461-64 (2004); Mei & Wolf, J. Am. Chem. Soc. 126:14736-37 (2004); Li et al., Angew. Chem. Int. Ed. 44:1690-93 (2005); Tumambac & Wolf, Org. Lett. 7:4045-48 (2005); Mei et al., J. Org. Chem. 71:2854-61 (2006); Mei & Wolf, Tetrahedron Lett. 47:7901-04 (2006); Wolf et al., Chem. Commun. 40:4242-44 (2006); Liu et al., J. Org. Chem. 73:4267-70 (2008); Yu & Pu, J. Am. Chem. Soc. 132:17698-700 (2010); Wu et al., Chem. Eur. J. 17:7632-44 (2011); Yang et al., Org. Lett. 13:3510-13 (2011); He et al., Chem. Commun. 47:11641-43 (2011); Wanderley et al., J. Am. Chem. Soc. 134:9050-53 (2012); Pu, Review, Chem. Rev. 104:1687-716 (2004)), UV absorbance (Zhu & Anslyn, J. Am. Chem. Soc. 126:3676-77 (2004); Mei & Wolf, J. Am. Chem. Soc. 128:13326-27 (2006); Leung et al., J. Am. Chem. Soc. 130:12318-27 (2008); Leung & Anslyn, J. Am. Chem. Soc. 130:12328-33 (2008); Iwaniuk et al., J. Org. Chem. 77:5203-08 (2012)), and circular dichroism (Superchi et al., Angew. Chem. Int. Ed. 40:451-54 (2001); Kurtan et al., J. Am. Chem. Soc. 123:5974-82 (2001); Huang et al., J. Am. Chem. Soc. 124:10320-35 (2002); Mazaleyrat et al., J. Am. Chem. Soc. 126:12874-79 (2004); Superchi et al., J. Am. Chem. Soc. 128:6893-902 (2006); Holmes et al., J. Am. Chem. Soc. 129:1506-07 (2007); Dutot et al., J. Am. Chem. Soc. 130:5986-92 (2008); Kim et al., Angew. Chem. Int. Ed. 47:8657-60 (2008); Waki et al., Angew. Chem. Int. Ed. 46:3059-61 (2007); Katoono et al., J. Am. Chem. Soc. 131:16896-904 (2009); Ghosn & Wolf, J. Am. Chem. Soc. 131:16360-61 (2009); Ghosn & Wolf, Tetrahedron 66:3989-94 (2010); Ghosn & Wolf, J. Org. Chem. 76:3888-97 (2011); Ghosn & Wolf, Tetrahedron 67:6799-803 (2011); Joyce et al., J. Am. Chem. Soc. 133:13746-52 (2011); You et al., J. Am. Chem. Soc. 134:7117-25 (2012); Wezenberg et al., Angew. Chem. Int. Ed. 50:713-16 (2011); Iwaniuk & Wolf, J. Am. Chem. Soc. 133:2414-17 (2011); Iwaniuk & Wolf, Org. Lett. 13:2602-05 (2011); Iwaniuk et al., Chirality 24:584-89 (2012); Li et al., J. Am. Chem. Soc. 134:9026-29 (2012); Iwaniuk & Wolf, Chem. Commun. 48:11226-28 (2012)).
Circular dichroism spectroscopy is one of the most powerful techniques commonly used for elucidation of the three-dimensional structure, molecular recognition events, and stereodynamic processes of chiral compounds (Gawroński & Grajewski, Org. Lett. 5:3301-03 (2003); Allenmark, Chirality 15:409-22 (2003); Berova et al., Chem. Soc. Rev. 36:914-31 (2007)). The potential of chiroptical CD (circular dichroism) and CPL (circular polarized luminescence) assays with carefully designed probes that produce a circular dichroism signal upon recognition of a chiral substrate has received increasing attention in recent years, and bears considerable promise with regard to high-throughput ee screening (Nieto et al., J. Am. Chem. 130:9232-33 (2008); Leung et al., Chem. Soc. Rev. 41:448-79 (2012); Song et al., Chem. Commun. 49:5772-74 (2013) (chirality CPL sensing)).
Many examples of chirality chemosensing with stereodynamic molecular receptors or supramolecular arrangements that generate a characteristic CD signal upon covalent or non-covalent binding of a target compound have been reported (e.g., Bentley & Wolf, J. Am. Chem. Soc. 135:12200 (2013); Ghosn & Wolf, J. Am. Chem. Soc. 131:16360 (2009); Ghosn & Wolf, J. Org. Chem. 76:3888 (2011); Ghosn & Wolf, Tetrahedron 67:6799 (2011); Hembury et al., Review, Chem. Rev. 108:1-73 (2008) (supramolecular sensors); Holmes et al., Chirality 14:471 (2002); Iwaniuk & Wolf, Chem. Commun. 48:11226 (2012); Iwaniuk & Wolf, J. Am. Chem. Soc. 133:2414 (2011); Iwaniuk & Wolf, Org. Lett. 13:2602 (2011); Iwaniuk et al., Chirality 24:584 (2012); Katoono et al., Tetrahedron Lett. 47:1513-18 (2006); Kawai et al., Chem. Eur. J. 11:815-24 (2005); Kohmoto et al., Tetrahedron Lett. 49:1223-27 (2008); Leung & Anslyn, Org. Lett. 13:2298 (2011); Matile et al., J. Am. Chem. Soc. 33:2072 (1993); Nieto et al., J. Am. Chem. Soc. 130:9232 (2008); Tartaglia et al., J. Org. Chem. 73:4865 (2008); Tartaglia et al., Org. Lett. 10:3421-24 (2008); Tumambac et al., Eur. J. Org. Chem. 3850-56 (2004); Wolf & Bentley, Review, Chem. Soc. Rev. 42:5408 (2013); Zhang & Wolf, Chem. Comm. 49:7010 (2013)). This includes biphenyl-derived probes that populate a thermodynamically favored chiral conformation upon reaction with one enantiomer of an amino acid, carboxylic acid, amine, or alcohol. This chiral induction process yields a Cotton effect that can be correlated to the absolute configuration of the covalently-bound substrate (Superchi et al., Angew. Chem. Int. Ed. 40:451-54 (2001); Hosoi et al., Tetrahedron Lett. 42:6315-17 (2001); Mazaleyrat et al., J. Am. Chem. Soc. 126:12874-79 (2004); Mazaleyrat et al., Chem. Eur. J. 11:6921-29 (2005); Superchi et al., J. Am. Chem. Soc. 128:6893-902 (2006); Dutot et al., J. Am. Chem. Soc. 130:5986-92 (2008); Kuwahara et al., Org. Lett. 15:5738-41 (2013)). Essentially the same concept has been exploited for chirality chemosensing by using molecular bevel gears (Sciebura et al., Angew. Chem. Int. Ed. 48:7069-72 (2009); Sciebura & Gawronski, Chem. Eur. J. 17:13138-41 (2011)), propellers (Katoono et al., J. Am. Chem. Soc. 131:16896-904 (2009)), or other probes that can afford a CD-active helical arrangement (Waki et al., Angew. Chem. Int. Ed. 46:3059-61 (2007); Tartaglia et al., Org. Lett. 10:3421-24 (2008); Kim et al., Angew. Chem. Int. Ed. 47:8657-60 (2008)). Similarly, a variety of intriguing stereodynamic chemosensors that generate strong CD signals in the presence of a chiral bias have been developed (Balaz et al., Angew. Chem. Int. Ed. 44:4006-09 (2005); Berova et al., Chem. Commun. 5958-80 (2009); Borovkov et al., J. Am. Chem. Soc. 123:2979-89 (2001); Canary et al., Chem. Commun. 46:5850-60 (2010); Holmes et al., J. Am. Chem. Soc. 129:1506-07 (2007); Huang et al., J. Am. Chem. Soc. 124:10320-35 (2002); Ishii et al., Chirality 17:305-15 (2005); Joyce et al., Chem. Eur. J. 18:8064-69 (2012); Joyce et al., J. Am. Chem. Soc. 133:13746-52 (2011); Katoono et al., Tetrahedron Lett. 47:1513-18 (2006); Kikuchi et al., J. Am. Chem. Soc. 114:1351-58 (1992); Kim et al., Chem. Commun. 49:11412-14 (2013); Kurtan et al., J. Am. Chem. Soc. 123:5962-73 (2001); Kurtan et al., J. Am. Chem. Soc. 123:5974-82 (2001); Li et al., J. Am. Chem. Soc. 130:1885-93 (2008); Li & Borhan, J. Am. Chem. Soc. 130:16126-27 (2008); Li et al., J. Am. Chem. Soc. 134:9026-29 (2012); Nieto et al., Chem. Eur. J. 16:227-32 (2010); Proni et al., Chem. Commun. 1590-91 (2002); Proni et al., J. Am. Chem. Soc. 125:12914-27 (2003); Tamiaki et al., Tetrahedron 59:10477-83 (2003); Tsukube et al., J. Chem. Soc. Dalton Trans. 1:11-12 (1999); Waki et al., Angew. Chem. Int. Ed. 46:3059-61 (2007); Wezenberg et al., Angew. Chem. Int. Ed. 50:713-16 (2011); Yang et al., Org. Lett. 4:3423-26 (2002); You et al., J. Am. Chem. Soc. 134:7117-25 (2012); You et al., J. Am. Chem. Soc. 134:7126-34 (2012); You et al., Nat. Chem. 3:943-48 (2011); Zhang et al., Chirality 15:180-89 (2003)). In many cases, the CD output of the chemosensor allows determination of the absolute configuration and the enantiomeric composition of the chiral analyte (Wolf & Bentley, Chem. Soc. Rev. 42:5408-24 (2013)).
But the analysis of the concentration and the enantiomeric composition of chiral substrates by a single optical chemosensor is a difficult task, and a practical method that is applicable to many chiral compounds and avoids time consuming derivatization and purification steps is very desirable (Nieto et al., Org. Lett. 10:5167-70 (2008); Nieto et al., Chem. Eur. J. 16:227-32 (2010); Yu et al., J. Am. Chem. Soc. 134:20282-85 (2012)). Despite the general usefulness of tropos ligands in asymmetric catalysis, their potential as induced circular dichroism probes for fast concentration and ee analysis has remained unexplored. Achiral (salen)cobalt complexes have also not been used to probe chirality and to determine ee's.
The present invention is directed to overcoming these and other deficiencies in the art.